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Medulloblastoma (MB) stands as one of the prevalent malignant brain tumors among pediatric patients. Despite its prevalence, the intricate interplay between the regulatory program driving malignancy in MB cells and their interactions with the microenvironment remains insufficiently understood. Leveraging the capabilities of single‐cell Assay for Transposase‐Accessible Chromatin sequencing (scATAC‐seq), the chromatin accessibility landscape is unveiled across 59,015 distinct MB cells. This expansive dataset encompasses cells belonging to discrete molecular subgroups, namely SHH, WNT, Group3, and Group4. Within these chromatin accessibility profiles, specific regulatory elements tied to individual subgroups are uncovered, shedding light on the distinct activities of transcription factors (TFs) that likely orchestrate the tumorigenesis process. Moreover, it is found that certain neurotransmitter receptors (NTRs) are subgroup‐specific and can predict MB subgroup classification when combined with their associated transcription factors. Notably, targeting essential NTRs within tumors influences both the in vitro sphere‐forming capability and the in vivo tumorigenic capacity of MB cells. These findings collectively provide fresh insights into comprehending the regulatory networks and cellular dynamics within MBs. Furthermore, the significance of the TF‐NTR regulatory circuits is underscored as prospective biomarkers and viable therapeutic targets. [ABSTRACT FROM AUTHOR]

Patients with brain cancers including medulloblastoma lack treatments that are effective long‐term and without side effects. In this study, a multifunctional fluoropolymer‐engineered iron oxide nanoparticle gene‐therapeutic platform is presented to overcome these challenges. The fluoropolymers are designed and synthesized to incorporate various properties including robust anchoring moieties for efficient surface coating, cationic components to facilitate short interference RNA (siRNA) binding, and a fluorinated tail to ensure stability in serum. The blood‐brain barrier (BBB) tailored system demonstrates enhanced BBB penetration, facilitates delivery of functionally active siRNA to medulloblastoma cells, and delivers a significant, almost complete block in protein expression within an in vitro extracellular acidic environment (pH 6.7) – as favored by most cancer cells. In vivo, it effectively crosses an intact BBB, provides contrast for magnetic resonance imaging (MRI), and delivers siRNA capable of slowing tumor growth without causing signs of toxicity – meaning it possesses a safe theranostic function. The pioneering methodology applied shows significant promise in the advancement of brain and tumor microenvironment‐focused MRI‐siRNA theranostics for the better treatment and diagnosis of medulloblastoma. [ABSTRACT FROM AUTHOR]

Brain tumors are devastating diseases of the central nervous system. Brain tumor pathogenesis depends on both tumor‐intrinsic oncogenic programs and extrinsic microenvironmental factors, including neurons and glial cells. Glial cells (oligodendrocytes, astrocytes, and microglia) make up half of the cells in the brain, and interact with neurons to modulate neurodevelopment and plasticity. Many brain tumor cells exhibit transcriptomic profiles similar to macroglial cells (oligodendrocytes and astrocytes) and their progenitors, making them likely to subvert existing neuron–glial interactions to support tumor pathogenesis. For example, oligodendrocyte precursor cells, a putative glioma cell of origin, can form bona fide synapses with neurons. Such synapses are recently identified in gliomas and drive glioma pathophysiology, underscoring how brain tumor cells can take advantage of neuron–glial interactions to support cancer progression. In this review, it is briefly summarized how neurons and their activity normally interact with glial cells and glial progenitors, and it is discussed how brain tumor cells utilize neuron–glial interactions to support tumor initiation and progression. Unresolved questions on these topics and potential avenues to therapeutically target neuron–glia–cancer interactions in the brain are also pointed out. [ABSTRACT FROM AUTHOR]

Understanding childhood ependymomas: Children with posterior fossa group A (PFA) ependymomas have a dismal prognosis. PFAs overexpress the protein EZHIP (EZH inhibitory protein), and Panwalkar and colleagues investigated whether EZHIP could epigenetically rewire metabolic pathways. Glycolysis and tricarboxylic acid (TCA) cycle metabolism were enhanced in tumors with high EZHIP expression, associated with enrichment of histone H3 lysine 27 acetylation at hexokinase-2, pyruvate dehydrogenase, and AMPKα-2. The antidiabetic drug metformin, an AMPK activator, altered histone marks, lowered EZHIP concentrations, and suppressed TCA cycle metabolism, with decreased tumor volumes and increased survival in mice carrying patient-derived xenografts. These findings suggest that targeting integrated epigenetic and metabolomic pathways could be a therapeutic strategy for children with PFAs. Childhood posterior fossa group A ependymomas (PFAs) have limited treatment options and bear dismal prognoses compared to group B ependymomas (PFBs). PFAs overexpress the oncohistone-like protein EZHIP (enhancer of Zeste homologs inhibitory protein), causing global reduction of repressive histone H3 lysine 27 trimethylation (H3K27me3), similar to the oncohistone H3K27M. Integrated metabolic analyses in patient-derived cells and tumors, single-cell RNA sequencing of tumors, and noninvasive metabolic imaging in patients demonstrated enhanced glycolysis and tricarboxylic acid (TCA) cycle metabolism in PFAs. Furthermore, high glycolytic gene expression in PFAs was associated with a poor outcome. PFAs demonstrated high EZHIP expression associated with poor prognosis and elevated activating mark histone H3 lysine 27 acetylation (H3K27ac). Genomic H3K27ac was enriched in PFAs at key glycolytic and TCA cycle–related genes including hexokinase-2 and pyruvate dehydrogenase. Similarly, mouse neuronal stem cells (NSCs) expressing wild-type EZHIP (EZHIP-WT) versus catalytically attenuated EZHIP-M406K demonstrated H3K27ac enrichment at hexokinase-2 and pyruvate dehydrogenase, accompanied by enhanced glycolysis and TCA cycle metabolism. AMPKα-2, a key component of the metabolic regulator AMP-activated protein kinase (AMPK), also showed H3K27ac enrichment in PFAs and EZHIP-WT NSCs. The AMPK activator metformin lowered EZHIP protein concentrations, increased H3K27me3, suppressed TCA cycle metabolism, and showed therapeutic efficacy in vitro and in vivo in patient-derived PFA xenografts in mice. Our data indicate that PFAs and EZHIP-WT–expressing NSCs are characterized by enhanced glycolysis and TCA cycle metabolism. Repurposing the antidiabetic drug metformin lowered pathogenic EZHIP, increased H3K27me3, and suppressed tumor growth, suggesting that targeting integrated metabolic/epigenetic pathways is a potential therapeutic strategy for treating childhood ependymomas. [ABSTRACT FROM AUTHOR]

Combined treatment for medulloblastoma: Certain subtypes of medulloblastoma (MB) have poor treatment outcome. To identify better treatments, Endersby et al. now screened more than 3000 compounds using six different human MB cell lines and showed that inhibitors of cell cycle checkpoint kinases (CHK1/2) increased the efficacy of clinical treatments. In vivo, the combined treatment increased DNA damage and apoptosis, resulting in increased survival and reduced tumor volume in multiple models. The results suggest that CHK1/2 inhibition could be used to increase the efficacy of standard chemotherapeutics for treating MB. Medulloblastoma (MB) consists of four core molecular subgroups with distinct clinical features and prognoses. Treatment consists of surgery, followed by radiotherapy and cytotoxic chemotherapy. Despite this intensive approach, outcome remains dismal for patients with certain subtypes of MB, namely, MYC-amplified Group 3 and TP53-mutated SHH. Using high-throughput assays, six human MB cell lines were screened against a library of 3208 unique compounds. We identified 45 effective compounds from the screen and found that cell cycle checkpoint kinase (CHK1/2) inhibition synergistically enhanced the cytotoxic activity of clinically used chemotherapeutics cyclophosphamide, cisplatin, and gemcitabine. To identify the best-in-class inhibitor, multiple CHK1/2 inhibitors were assessed in mice bearing intracranial MB. When combined with DNA-damaging chemotherapeutics, CHK1/2 inhibition reduced tumor burden and increased survival of animals with high-risk MB, across multiple different models. In total, we tested 14 different models, representing distinct MB subgroups, and data were validated in three independent laboratories. Pharmacodynamics studies confirmed central nervous system penetration. In mice, combination treatment significantly increased DNA damage and apoptosis compared to chemotherapy alone, and studies with cultured cells showed that CHK inhibition disrupted chemotherapy-induced cell cycle arrest. Our findings indicated CHK1/2 inhibition, specifically with LY2606368 (prexasertib), has strong chemosensitizing activity in MB that warrants further clinical investigation. Moreover, these data demonstrated that we developed a robust and collaborative preclinical assessment platform that can be used to identify potentially effective new therapies for clinical evaluation for pediatric MB. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a severe complication of systemic sclerosis (SSc) associated with high morbidity and mortality. There are several biomarkers of SSc-PAH, reflecting endothelial physiology, inflammation, immune activation, extracellular matrix, metabolic changes, or cardiac involvement. Biomarkers associated with diagnosis, disease severity and progression have been identified, however, very few have been tested in a prospective setting. Some antinuclear antibodies such as nucleosome antibodies (NUC), anti-centromere antibodies (CENP-A/B) and anti-U3-ribonucleoprotein (anti-U3-RNP) are associated with PAH while anti-U1-ribonucleoprotein (anti-U1-RNP) is associated with a reduced PAH risk. Anti-endothelin receptor and angiotensin-1 receptor antibodies might be good markers of SSc-PAH and progression of pulmonary vasculopathy. Regarding the markers reflecting immune activation and inflammation, there are many inconsistent results. CXCL-4 was associated with SSc progression including PAH and lung fibrosis. Growth differentiation factor (GDF)-15 was associated with PAH and mortality but is not specific for SSc. Among the metabolites, kynurenine was identified as diagnostic marker for PAH, however, its pathologic role in the disease is unclear. Endostatin, an angiostatic factor, was associated with heart failure and poor prognosis. Established heart related markers, such as N-terminal fragment of A-type natriuretic peptide/brain natriuretic peptide (NT-proANP, NT-proBNP) or troponin I/T are elevated in SSc-PAH but are not specific for the right ventricle and may be increased to the same extent in left heart disease. Taken together, there is no universal specific biomarker for SSc-PAH, however, there is a pattern of markers that is strongly associated with a risk of vascular complications in SSc patients. Further comprehensive, multicenter and prospective studies are warranted to develop reliable algorithms for detection and prognosis of SSc-PAH. [ABSTRACT FROM AUTHOR]

Lung illness encountered in patients with rheumatic diseases bears clinical significance in terms of increased morbidity and mortality as well as potential challenges placed on patient care. Although our understanding of natural history of this important illness is still limited, epidemiologic knowledge has been accumulated during the past decade to provide useful information on the risk factors and prognosis of lung involvements in rheumatic diseases. Moreover, the pathogenesis particularly in the context of genetics has been greatly updated for both the underlying rheumatic disease and associated lung involvement. This review will focus on the current update on the epidemiologic and genetics features and treatment options of the lung involvements associated with four major rheumatic diseases (rheumatoid arthritis, systemic sclerosis, myositis, and systemic lupus erythematosus), with more attention to a specific form of involvement or interstitial lung disease. [ABSTRACT FROM AUTHOR]

Brain tumors are among the leading causes of cancer-related deaths in children. Although surgery, aggressive radiation, and chemotherapy have improved outcomes, many patients still die of their disease. Moreover, thosewho survive often suffer devastating long-term side effects from the therapies. A greater understanding of the molecular underpinnings of these diseases will drive the development of new therapeutic approaches. Advances in genomics and epigenomics have provided unprecedented insight into themolecular diversity of these diseases and, in several cases, have revealed key genes and signaling pathways that drive tumor growth. These not only serve as potential therapeutic targets but also have facilitated the creation of animal models that faithfully recapitulate the human disease for preclinical studies. In this Review, we discuss recent progress in understanding the molecular basis of the three most common malignant pediatric brain tumors-medulloblastoma, ependymoma, and high-grade glioma-and the implications for development of safer and more effective therapies. [ABSTRACT FROM AUTHOR]

Autophagy is a catabolic process mediated by lysosomal degradation and is a key player in regulating cellular metabolism during cancer progression. Autophagy maintains cellular homeostasis by degrading unnecessary cellular molecules, which also prevents tumorigenesis. Conversely, autophagy also provides nutrients that support malignant tumor growth in advanced tumors. Multiple novel mechanisms have been proposed to explain the tumor-facilitating role of autophagy. Autophagy regulates diverse metabolic pathways that promote tumor proliferation and survival, which are closely associated with oncogenic activators and tumor suppressors. Autophagy has been implicated in cancer cell invasion and metastasis. Accordingly, autophagy has emerged as a tumor-promoting mechanism that facilitates cancer cell growth and survival. Mechanistic studies of autophagy during tumor progression may identify potential targets that can be utilized to disrupt cancer development. Understanding the molecular networks integrating metabolic changes and autophagy in cancer cells could provide novel insights to enhance targeted cancer therapies. [ABSTRACT FROM AUTHOR]

Choroid plexus papillomas (CPPs) and carcinomas (CPCs) are rare neoplasms that affect mostly children. Due to their rarity, their epidemiology and outcomes are incompletely understood. The National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) Program is a well-established population-based group of registries that collects and publishes cancer incidence and survival data representing approximately 28 % of the US population. SEER-STAT v8.1.2 was used to identify patients with ICD-O-3 codes for choroid plexus tumors in patients aged 0-19. Demographics, initial treatment, and follow-up data were collected. Statistical methods including Kaplan-Meier curves, log rank tests, and Cox proportional hazards regression were used to estimate associations between independent variables and survival. The SEER registries contained 107 CPPs (2004-2010) and 95 CPCs (1978-2010). Median follow-up was 38 and 40 months, respectively. More than 75 % of CPCs were diagnosed before the age of 5 years, versus 48 % for CPPs. Sixty-five percent of CPCs and 57 % of CPPs occurred in males. In both groups at least 90 % of children underwent surgical resection. Gross total resection (GTR) was achieved in 67.0 % of CPCs and 63.6 % of CPPs. Almost 17 % of CPCs were treated with radiation versus only 0.9 % of CPPs. More than 98 % of patients with CPP were alive at the last follow-up, versus 62 % of CPC patients. For CPC, surgery was significantly associated with increased overall survival, but contrary to previous reports, extent of surgical resection was not associated with survival. Age, sex, race, and radiation treatment also had no effect on survival. This report, using the SEER datasets, corroborates many findings of previous smaller studies on CPTs. CPC occurs in younger children, with a male predominance, and a much worse prognosis than CPP. As such, these tumors have been treated aggressively with high rates of GTR and radiation treatment. Despite these treatments, overall survival for CPC remains poor. [ABSTRACT FROM AUTHOR]

Better understanding of ependymoma (EPN) biology at relapse is needed to improve therapy at this critical event. Convincing data exist defining transcriptionally distinct posterior fossa (PF) sub-groups A and B at diagnosis. The clinical and biological consequence of these sub-groups at recurrence has not yet been defined. Genome and transcriptome microarray profiles and clinical variables of matched primary and first recurrent PF EPN pairs were used to identify biologically distinct patterns of progression between EPN sub-groups at recurrence. Key findings were validated by histology and immune function assays. Transcriptomic profiles were partially conserved at recurrence. However, 4 of 14 paired samples changed sub-groups at recurrence, and significant sub-group-specific transcriptomic changes between primary and recurrent tumors were identified, which were predominantly immune-related. Further examination revealed that Group A primary tumors harbor an immune gene signature and cellular functionality consistent with an immunosuppressive phenotype associated with tissue remodeling and wound healing. Conversely, Group B tumors develop an adaptive, antigen-specific immune response signature and increased T-cell infiltration at recurrence. Clinical distinctions between sub-groups become more apparent after first recurrence. Group A tumors were more often sub-totally resected and had a significantly shorter time to subsequent progression and worse overall survival. Minimal tumor-specific genomic changes were observed for either PF Groups A or B at recurrence. Molecular sub-groups of PF EPN convey distinct immunobiologic signatures at diagnosis and recurrence, providing potential biologic rationale to their disparate clinical outcomes. Immunotherapeutic approaches may be warranted, particularly in Group A PF EPN. [ABSTRACT FROM AUTHOR]

Outcomes for children with relapsed ependymoma are poor. Re-irradiation is a potentially viable salvage option in these patients. Data were reviewed for 12 patients (median age 5.6 years) with relapsed ependymoma who received fractionated stereotactic radiosurgery (fSRS) following maximal surgical resection from 1995 to 2012. Four patients experienced a second recurrence, including 2 in-field and 2 distant failures. Median time to second recurrence (32 months) was significantly longer than time to first recurrence (24 months) ( p = 0.008). Three-year local control was 89 %, and median event free survival from fSRS was 3.4 years. Radiation necrosis was observed in 6 patients, 3 who were symptomatic. In conclusion, fSRS offers durable response with a tolerable toxicity profile in children with recurrent EPN. [ABSTRACT FROM AUTHOR]

Diffuse intrinsic pontine glioma (DIPG) is a brain cancer with a median survival of only 1 year. Lack of molecular characterization of this tumor impedes the development of novel therapies. Membrane protein B7-H3, aka CD276, involved in interactions with host defenses in certain cancers, has been shown to be over-expressed in the majority of malignant neuroectodermal tumors including adult high-grade glioma. Targeting B7-H3 with a monoclonal antibody has demonstrated safety and efficacy in the salvage treatment of stage IV childhood neuroblastoma, another neuroectodermal tumor. It thus stands to reason that B7-H3 might serve as a therapeutic target in DIPG. B7-H3 immunoreactivity was determined in DIPG and non-diffuse brainstem glioma specimens with immunohistochemistry. In addition, B7-H3 mRNA expression was evaluated with microarrays in another set of specimens. All of the nine (100 %) DIPG specimens were shown to be B7-H3 immunoreactive. In the non-diffuse brainstem glioma group, none of the eight WHO grade I specimens showed B7-H3 immunoreactivity and nine of the 24 WHO grade II specimens (37.5 %) showed B7-H3 immunoreactivity. The association between histological grade and B7-H3 immunoreactivity was statistically highly significant. B7-H3 mRNA expression was also significantly higher in DIPG samples than in normal brain and juvenile pilocytic astrocytoma (WHO grade I) specimens. In summary, B7-H3 is over-expressed in DIPG. Given the need for novel treatment in this disease, antibody-based immunotherapy against B7-H3 in DIPG warrants further investigation. [ABSTRACT FROM AUTHOR]

Craniopharyngioma is histologically benign and associated with high survival rates but poor quality of life. The SEER Program is among the most cited data sources regarding malignancies in the United States. SEER began collecting data regarding craniopharyngiomain 2004. SEER-STAT v7.0.5 was utilized to identify patients (January 1, 2004-December 31, 2008) with ICD-O-3 codes for craniopharyngioma. Age was categorized into 3 groups: ≤19, 20-34, and ≥35 years, as was surgical intervention: none, subtotal resection, and gross total/radical resection. Demographic, initial treatment, and follow-up data were collected. 635/662 (95.9 %) patients had complete data. Incidence per million patient-years by age group was 1.9, 1.1, and 1.9, respectively ( p < 0.0001). There was bimodal incidence, with peaks at 5-9 and 60-74 years. Surgery occurred in 528 patients (83.1 %), without association between age group and extent of surgery ( p = 0.14). Radiation was delivered in 139 (21.9 %) cases, with no association between treatment and extent of surgery ( p = 0.73) or age group ( p = 0.14). Median follow-up was 23 months. Overall and Cause-specific Survival were 87.9 and 94.5 %, respectively. Neither was associated with extent of surgery but both were positively associated with radiation ( p = 0.0003 and 0.0007, respectively). There was no difference in OS or CSS when comparing STR ± RT versus GTR alone ( p = 0.38 and 0.56, respectively). SEER provides reliable demographic and survival data regarding craniopharyngioma. SEER's focus on mortality statistics limits utility for outcomes studies in tumors with high survival rates, such as craniopharyngioma. Initial treatment data from SEER varies somewhat from current literature, meriting further investigation. [ABSTRACT FROM AUTHOR]

Malignant glioma, or glioblastoma, is the most common and lethal formof brain tumor with amedian survival time of 15months. The established therapeutic regimen includes a tripartite therapy of surgical resection followed by radiation and temozolomide (TMZ) chemotherapy, concurrently with radiation and then as an adjuvant. TMZ, a DNA alkylating agent, is the most successful antiglioma drug and has added several months to the life expectancy of malignant glioma patients. However, TMZ is also responsible for inducing lymphopenia and myelosuppression in malignant glioma patients undergoing chemotherapy. Although TMZ-induced lymphopenia has been attributed to facilitate antitumor vaccination studies by inducing passive immune response, in general lymphopenic conditions have been associated with poor immune surveillance leading to opportunistic infections in glioma patients, as well as disrupting active antiglioma immune response by depleting both T and NK cells. Deletion of O6- methylguanine-DNA-methyltransferase (MGMT) activity, a DNA repair enzyme, by temozolomide has been determined to be the cause of lymphopenia. Drug-resistant mutation of the MGMT protein has been shown to render chemoprotection against TMZ. The immune modulating role of TMZ during glioma chemotherapy and possible mechanisms to establish a strong TMZ-resistant immune response have been discussed. [ABSTRACT FROM AUTHOR]

A primary culture from rat renal IMCD cells was established to investigate the permeability characteristics of the luminal and contraluminal plasma membranes of the papillary collecting duct in vitro. Freshly isolated IMCD cells were grown on filters in a special “epithelial cell” medium. Confluency was proved with an epithelial volt/ohm meter. After 7 d of culture the transepithelial resistance reached more than 1000 Ω×cm2. A polarization of the cells with regard to a basolateral localization of a lactate efflux system, and an l-alanine transport system was achieved. The hypotonicity-activated release systems for the organic osmolytes sorbitol and betaine were also located basolaterally, whereas taurine, glycerophosphorylcholine, and myo-inositol left the cells at both cell poles but with different capacity. Morphological observations revealed also that the monolayer was well differentiated. Thus, a model of a renal collecting duct epithelium was established which can be used to analyze polarized and differentiated transport processes across the epithelial cells and their plasma membranes. [ABSTRACT FROM AUTHOR]

Among the diverse forms of lung involvement, interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are two important conditions in patients with rheumatic diseases that are associated with significant morbidity and mortality. The management of ILD and PAH is challenging because the current treatment often provides only limited patient survival benefits. Such challenges derive from their common pathogenic mechanisms, where not only the inflammatory processes of immune cells but also the fibrotic and proliferative processes of nonimmune cells play critical roles in disease progression, making immunosuppressive therapy less effective. Recently, updated treatment strategies adopting targeted agents have been introduced with promising results in clinical trials for ILD ad PAH. This review discusses the epidemiologic features of ILD and PAH among patients with rheumatic diseases (rheumatoid arthritis, myositis, and systemic sclerosis) and the state-of-the-art treatment options, focusing on targeted agents including biologics, antifibrotic agents, and vasodilatory drugs. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by dysregulation of the immune system, vascular damage, and fibrosis of the skin and internal organs. Patients with SSc show a heterogeneous phenotype and a range of clinical courses. Therefore, biomarkers that are helpful for precise diagnosis, prediction of clinical course, and evaluation of the therapeutic responsiveness of disease are required in clinical practice. SSc-specific autoantibodies are currently used for diagnosis and prediction of clinical features, as other biomarkers have not yet been fully vetted. Krebs von den Lungen-6 (KL-6), surfactant protein-D (SP-D), and CCL18 have been considered as serum biomarkers of SSc-related interstitial lung disease. Moreover, levels of circulating brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) can provide diagnostic information and indicate the severity of pulmonary arterial hypertension. Assessment of several serum/plasma cytokines, chemokines, growth factors, adhesion molecules, and other molecules may also reflect the activity or progression of fibrosis and vascular involvement in affected organs. Recently, microRNAs have also been implicated as possible circulating indicators of SSc. In this review, we focus on several potential SSc biomarkers and discuss their clinical utility. [ABSTRACT FROM AUTHOR]

Circulating selenoprotein P (SELENOP) constitutes an established biomarker of Se status. SELENOP concentrations are reduced in inflammation and severe disease. Recently, elevated SELENOP levels have been suggested as diagnostic marker and therapeutic target in pulmonary arterial hypertension (PAH). We decided to re-evaluate this hypothesis. A group of healthy controls (n = 30) was compared with patients suffering from systemic sclerosis (SSc, n = 66), one third with SSc-related PAH. Serum was analysed for trace elements and protein biomarkers, namely SELENOP, glutathione peroxidase 3 (GPx3) and ceruloplasmin (CP). Compared to controls, patients with SSc-related PAH displayed reduced serum Se (91 ± 2 vs. 68 ± 2 µg/L) and SELENOP concentrations (3.7 ± 0.8 vs. 2.7 ± 0.9 mg/L), along with lower GPx3 activity (278 ± 40 vs. 231 ± 54 U/L). All three biomarkers of Se status were particularly low in patients with skin involvement. Serum Cu was not different between the groups, but patients with SSc-related PAH showed elevated ratios of Cu/Se and CP/SELENOP as compared to controls. Our data indicate that patients with SSc-related PAH are characterized by reduced Se status in combination with elevated CP, in line with other inflammatory diseases. Further analyses are needed to verify the diagnostic value of these TE-related biomarkers in PAH. [ABSTRACT FROM AUTHOR]

Autophagy is a conserved process that is critical for sequestering and degrading proteins, damaged or aged organelles, and for maintaining cellular homeostasis under stress conditions. Despite its dichotomous role in health and diseases, autophagy usually promotes growth and progression of advanced cancers. In this context, clinical trials using chloroquine and hydroxychloroquine as autophagy inhibitors have suggested that autophagy inhibition is a promising approach for treating advanced malignancies and/or overcoming drug resistance of small molecule therapeutics (i.e., chemotherapy and molecularly targeted therapy). Efficient delivery of autophagy inhibitors may further enhance the therapeutic effect, reduce systemic toxicity, and prevent drug resistance. As such, nanocarrier‐based drug delivery systems have several distinct advantages over free autophagy inhibitors that include increased circulation of the drugs, reduced off‐target systemic toxicity, increased drug delivery efficiency, and increased solubility and stability of the encapsulated drugs. With their versatile drug encapsulation and surface‐functionalization capabilities, nanocarriers can be engineered to deliver autophagy inhibitors to tumor sites in a context‐specific and/or tissue‐specific manner. This review focuses on the role of nanomaterials utilizing autophagy inhibitors for cancer therapy, with a focus on their applications in different cancer types. Autophagy is a conserved process that is critical for sequestering and degrading proteins, damaged or aged organelles, and for capturing nanoparticles. Clinical trials have suggested that autophagy inhibition is a promising approach for treating advanced malignancies. With their versatile drug encapsulation and surface‐functionalization capabilities, nanocarrier‐based delivering of autophagy inhibitors has several distinct advantages over free autophagy inhibitors. [ABSTRACT FROM AUTHOR]